Pregnant women are more likely to become infected with Plasmodium falciparum than non-pregnant women. The mechanism responsible for their increased susceptibility is unknown, but pregnancy-associated hormones are considered to be important because they down-regulate innate and acquired immune responses. Little information is available on which hormone(s) are responsible, the nature of the specific antimalarial immune response(s) altered, or how they influence susceptibility to malaria. One of the major consequences of P. falciparum malaria during pregnancy is an increased risk of preterm deliveries (PTD). Infants born prematurely are at a significant risk of dying during their first year of life. Since pregnancy associated hormones play a key role in controlling the timing of parturition, P. falciparum parasites either directly or indirectly stimulate them to initiate labor prematurely. Mechanisms by which parasites alter the sequence of events leading to PTD have not been studied. After considering immune responses that are important in immunity to malaria and how specific hormones might down-regulate them, we developed a hypothetical model to explain how human chorionic gonadotropin, cortisol and prolactin might interact to suppress immune responses that result in susceptibility to malaria. We also developed a theoretical model on how malarial parasites could up-regulate corticotrophin-releasing hormone from syncytiotrophoblasts and initiate events leading to PTD. These are only two of numerous models that could be proposed and are highly exploratory. Thus, the primary aim of this R21 application is to use clinical data and specimens already collected, through our on-going research in pregnant Cameroonian women, in key experiments that will help test these models. If either model proves to be correct, it would open the door to new avenues of research, help identify antimalarial immune responses that are important during pregnancy, and possibly provide diagnostic markers for identifying women who are at risk of malaria-associated PTD.